BACKGROUND Matrix metalloproteinases(MMPs)participate in the degradation of extracellular matrix compounds,maintaining the homeostasis between fibrogenesis and fibrolytic processes in the liver.However,there are few s...BACKGROUND Matrix metalloproteinases(MMPs)participate in the degradation of extracellular matrix compounds,maintaining the homeostasis between fibrogenesis and fibrolytic processes in the liver.However,there are few studies on the regulation of liver MMPs in fibrosis progression in humans.AIM To assess the production activity and regulation of matrix metalloproteinases in liver fibrosis stages in chronic hepatitis C(CHC).METHODS A prospective,cross-sectional,multicenter study was conducted.CHC patients were categorized in fibrosis grades through FibroTest®and/or FibroScan®.Serum MMP-2,-7,and-9 were determined by western blot and multiplex suspension array assays.Differences were validated by the Kruskal-Wallis and Mann-Whitney U tests.The Spearman correlation coefficient and area under the receiver operating characteristic curve were calculated.Collagenolytic and gelatinase activity was determined through the Azocoll substrate and zymogram test,whereas tissue inhibitor of metalloproteinase-1 production was determined by dot blot assays.RESULTS Serum concentrations of the MMPs evaluated were higher in CHC patients than in healthy subjects.MMP-7 distinguished early and advanced stages,with a correlation of 0.32(P<0.001),and the area under the receiver operating characteristic displayed moderate sensitivity and specificity for MMP-7 in F4(area under the receiver operating characteristic,0.705;95%confidence interval:0.605-0.805;P<0.001).Collagenolytic activity was detected at F0 and F1,whereas gelatinase activity was not detected at any fibrosis stage.Tissue inhibitor of metalloproteinase-1 determination showed upregulation in F0 and F1 but downregulation in F2(P<0.001).CONCLUSION High concentrations of inactive MMPs were present in the serum of CHC patients,reflecting the impossibility to restrain liver fibrosis progression.MMPs could be good diagnostic candidates and therapeutic targets for improving novel strategies to reverse liver fibrosis in CHC.展开更多
Objective To optimize the therapeutic dosage of tetrandrine (Tet) in rat hepatic fibrosis model. Methods 50 Wistar ratswere divided into 5 groups at random including normal control, model control, Tet-treated model gr...Objective To optimize the therapeutic dosage of tetrandrine (Tet) in rat hepatic fibrosis model. Methods 50 Wistar ratswere divided into 5 groups at random including normal control, model control, Tet-treated model groups of 10 mg.kg-1.d-1, 5 mg.kg-1.d-1and 2.5 mg.kg-1.d-1(n=10 in each group). All rats, except for the normal controls, were injected with axenic porcine serum(0.5ml each time, twice a week) intraperitoneally for8 weeks to establish hepatic fibrosis. After the 8th week, rats of Tet-treated modelgroups were given by gavage once a day with different doses of Tet for another8 weeks. Then the liver function, serum levels of hyaluron-ic acid (HA), laminin (LM), and procollagen type III (PCIII) were tested. Collagen type I and III, pathological changes in liver tissuewere also assessed. Results Most indices of liver function including alanine minotransferase ( ALT), aspartate aminotransferase(AST), albumin (ALB), albumin /globulin ratio (A/G) and alkaline phosphatase (ALP) improved significantly in Tet-treated groupswith the exception ofγ-glutamyl transpeptidase (γ-GT) and total bilirubin (TBIL). Secondly, markedly lowered levels of HA, LMandcollagen type I, III were also detected by radioimmunology and immunohistochemistry in the 5 mg.kg-1.d-1Tet-treated model group.Moreover, pathological findings confirmed the statistically significant improvement in hepatofibrotic degree resulted from the treatment of5 mg.kg-1.d-1rather than other doses of Tet. Conclusion For experimental Wistar rats, Tet exhibited an anti-hepatofibrotic action indoses within the range of 2.5 mg.kg-1.d-1to 10 mg.kg-1.d-1, and 5 mg.kg-1.d-1may be the optimum one among all doses.展开更多
Objective To clarify the actions of somatostatin (SST) on the hepatic fibrogenesis in experimental rats. Methods Seventy five Sprague-Dawley rats were divided into 5 groups at random, including normal control, model c...Objective To clarify the actions of somatostatin (SST) on the hepatic fibrogenesis in experimental rats. Methods Seventy five Sprague-Dawley rats were divided into 5 groups at random, including normal control, model control, SST-treated model groups of high, medium and low doses (200 μg·kg-1·d-1, 100 μg·kg-1·d-1 and 50 μg·kg-1·d-1, respectively) (n=15, in each group). All rats, except for the normal controls, were injected with 40% carbon tetrachloride (CCl4) subcutaneously for 8 weeks to establish hepatic fibrosis. Meanwhile, rats of SST-treated model groups were given different doses of SST twice a day in the same way. Then the liver function, serum levels of hyaluronic acid (HA), laminin (LM), and collagen type IV (CIV) were tested. The collagen types I and III, and pathological changes in liver tissue were assessed. Results Being compared with the model control group, SST-treated groups, especially the medium and low dose ones, exhibited significantly improved indices of liver function, including alanine minotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), total bilirubin (TBIL) and alkaline phosphatase (ALP). Markedly lowered expression of serum HA, LM and tissular collagen types I, III were also detected radioimmunologically and immunohistochemically in the low dose SST-treated model group. Moreover, pathological findings, such as lessened fibrous septa, decreased hepatic stellate cells (HSCs), alleviated hepatic steatosis and attenuated inflammation, confirmed the significant improvement in fibrotic degree under the treatment of low dose rather than other doses of SST.Conclusion SST exerts the negative modulatory effect on hepatic fibrosis with a pathophysiological basis of extracellular matrixes (ECM) decreasing and hepatocyte protection. Low dose of SST (50 μg·kg-1·d-1) may be the optimum one among all doses.展开更多
There have been considerable recent advances towards a better understanding of the complex cellular and molecular network underlying liver fibrogenesis.Recent data indicate that the termination of fibrogenic processes...There have been considerable recent advances towards a better understanding of the complex cellular and molecular network underlying liver fibrogenesis.Recent data indicate that the termination of fibrogenic processes and the restoration of deficient fibrolytic pathways may allow the reversal of advanced fibrosis and even cirrhosis.Therefore,efforts have been made to better clarify the cellular and molecular mechanisms that are involved in liver fibrosis.Activation of hepatic stellate cells(HSCs)remains a central event in fibrosis,complemented by other sources of matrix-producing cells,including portal fibroblasts,fibrocytes and bone marrow-derived myofibroblasts.These cells converge in a complex interaction with neighboring cells to provoke scarring in response to persistent injury.Defining the interaction of different cell types,revealing the effects of cytokines on these cells and characterizing the regulatory mechanisms that control gene expression in activated HSCs will enable the discovery of new therapeutic targets.Moreover,the characterization of different pathways associated with different etiologies aid in the development of disease-specific therapies.This article outlines recent advances regarding the cellular and molecular mechanisms involved in liver fibrosis that may be translated into future therapies.The pathogenesis of liver fibrosis associated with alcoholic liver disease,non-alcoholic fatty liver disease and viral hepatitis are also discussed to emphasize the various mechanisms involved in liver fibrosis.展开更多
Alcoholic liver disease(ALD)is a leading cause of liver disease and liver-related deaths globally,particularly in developed nations.Liver fibrosis is a consequence of ALD and other chronic liver insults,which can prog...Alcoholic liver disease(ALD)is a leading cause of liver disease and liver-related deaths globally,particularly in developed nations.Liver fibrosis is a consequence of ALD and other chronic liver insults,which can progress to cirrhosis and hepatocellular carcinoma if left un-treated.Liver fibrosis is characterized by accumulation of excess extracellular matrix components,including typeⅠcollagen,which disrupts liver microcirculation and leads to injury.To date,there is no therapy for the treatment of liver fibrosis;thus treatments that either prevent the accumulation of typeⅠcollagen or hasten its degradation are desirable.The focus of this review is to examine the regulation of typeⅠcollagen in fibrogenic cells of the liver and to discuss current advances in therapeutics to eliminate excessive collagen deposition.展开更多
Liver cirrhosis is a leading cause of death from liver‐related diseases accompanied by a variety of complications;however,hepatic fibrosis,an inevitable stage of cirrhosis,is possible to be reversed and cured.Hepatic...Liver cirrhosis is a leading cause of death from liver‐related diseases accompanied by a variety of complications;however,hepatic fibrosis,an inevitable stage of cirrhosis,is possible to be reversed and cured.Hepatic stellate cells(HSCs)are the primary cells that secrete extracellular matrix in the liver and play a dominant role in the pathogenesis of hepatic fibrosis.Effective therapeutic approaches for reversing hepatic fibrosis aim at inhibiting the activation of HSCs and inducing their inactivation or death.This review highlights the mechanism by which traditional Chinese medicine(TCM)regulates the activity of HSCs and exerts antifibrotic effects,providing insights and prospects for the treatment of hepatic fibrosis with TCM.展开更多
基金the National Council for Science and Technology,No.SALUD-2016-272579 and No.PAPIIT-UNAM TA200515.
文摘BACKGROUND Matrix metalloproteinases(MMPs)participate in the degradation of extracellular matrix compounds,maintaining the homeostasis between fibrogenesis and fibrolytic processes in the liver.However,there are few studies on the regulation of liver MMPs in fibrosis progression in humans.AIM To assess the production activity and regulation of matrix metalloproteinases in liver fibrosis stages in chronic hepatitis C(CHC).METHODS A prospective,cross-sectional,multicenter study was conducted.CHC patients were categorized in fibrosis grades through FibroTest®and/or FibroScan®.Serum MMP-2,-7,and-9 were determined by western blot and multiplex suspension array assays.Differences were validated by the Kruskal-Wallis and Mann-Whitney U tests.The Spearman correlation coefficient and area under the receiver operating characteristic curve were calculated.Collagenolytic and gelatinase activity was determined through the Azocoll substrate and zymogram test,whereas tissue inhibitor of metalloproteinase-1 production was determined by dot blot assays.RESULTS Serum concentrations of the MMPs evaluated were higher in CHC patients than in healthy subjects.MMP-7 distinguished early and advanced stages,with a correlation of 0.32(P<0.001),and the area under the receiver operating characteristic displayed moderate sensitivity and specificity for MMP-7 in F4(area under the receiver operating characteristic,0.705;95%confidence interval:0.605-0.805;P<0.001).Collagenolytic activity was detected at F0 and F1,whereas gelatinase activity was not detected at any fibrosis stage.Tissue inhibitor of metalloproteinase-1 determination showed upregulation in F0 and F1 but downregulation in F2(P<0.001).CONCLUSION High concentrations of inactive MMPs were present in the serum of CHC patients,reflecting the impossibility to restrain liver fibrosis progression.MMPs could be good diagnostic candidates and therapeutic targets for improving novel strategies to reverse liver fibrosis in CHC.
文摘Objective To optimize the therapeutic dosage of tetrandrine (Tet) in rat hepatic fibrosis model. Methods 50 Wistar ratswere divided into 5 groups at random including normal control, model control, Tet-treated model groups of 10 mg.kg-1.d-1, 5 mg.kg-1.d-1and 2.5 mg.kg-1.d-1(n=10 in each group). All rats, except for the normal controls, were injected with axenic porcine serum(0.5ml each time, twice a week) intraperitoneally for8 weeks to establish hepatic fibrosis. After the 8th week, rats of Tet-treated modelgroups were given by gavage once a day with different doses of Tet for another8 weeks. Then the liver function, serum levels of hyaluron-ic acid (HA), laminin (LM), and procollagen type III (PCIII) were tested. Collagen type I and III, pathological changes in liver tissuewere also assessed. Results Most indices of liver function including alanine minotransferase ( ALT), aspartate aminotransferase(AST), albumin (ALB), albumin /globulin ratio (A/G) and alkaline phosphatase (ALP) improved significantly in Tet-treated groupswith the exception ofγ-glutamyl transpeptidase (γ-GT) and total bilirubin (TBIL). Secondly, markedly lowered levels of HA, LMandcollagen type I, III were also detected by radioimmunology and immunohistochemistry in the 5 mg.kg-1.d-1Tet-treated model group.Moreover, pathological findings confirmed the statistically significant improvement in hepatofibrotic degree resulted from the treatment of5 mg.kg-1.d-1rather than other doses of Tet. Conclusion For experimental Wistar rats, Tet exhibited an anti-hepatofibrotic action indoses within the range of 2.5 mg.kg-1.d-1to 10 mg.kg-1.d-1, and 5 mg.kg-1.d-1may be the optimum one among all doses.
基金Supported by Scientific Development Programs of Science and Technology Commission of Shanghai(004119047)
文摘Objective To clarify the actions of somatostatin (SST) on the hepatic fibrogenesis in experimental rats. Methods Seventy five Sprague-Dawley rats were divided into 5 groups at random, including normal control, model control, SST-treated model groups of high, medium and low doses (200 μg·kg-1·d-1, 100 μg·kg-1·d-1 and 50 μg·kg-1·d-1, respectively) (n=15, in each group). All rats, except for the normal controls, were injected with 40% carbon tetrachloride (CCl4) subcutaneously for 8 weeks to establish hepatic fibrosis. Meanwhile, rats of SST-treated model groups were given different doses of SST twice a day in the same way. Then the liver function, serum levels of hyaluronic acid (HA), laminin (LM), and collagen type IV (CIV) were tested. The collagen types I and III, and pathological changes in liver tissue were assessed. Results Being compared with the model control group, SST-treated groups, especially the medium and low dose ones, exhibited significantly improved indices of liver function, including alanine minotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), total bilirubin (TBIL) and alkaline phosphatase (ALP). Markedly lowered expression of serum HA, LM and tissular collagen types I, III were also detected radioimmunologically and immunohistochemically in the low dose SST-treated model group. Moreover, pathological findings, such as lessened fibrous septa, decreased hepatic stellate cells (HSCs), alleviated hepatic steatosis and attenuated inflammation, confirmed the significant improvement in fibrotic degree under the treatment of low dose rather than other doses of SST.Conclusion SST exerts the negative modulatory effect on hepatic fibrosis with a pathophysiological basis of extracellular matrixes (ECM) decreasing and hepatocyte protection. Low dose of SST (50 μg·kg-1·d-1) may be the optimum one among all doses.
文摘There have been considerable recent advances towards a better understanding of the complex cellular and molecular network underlying liver fibrogenesis.Recent data indicate that the termination of fibrogenic processes and the restoration of deficient fibrolytic pathways may allow the reversal of advanced fibrosis and even cirrhosis.Therefore,efforts have been made to better clarify the cellular and molecular mechanisms that are involved in liver fibrosis.Activation of hepatic stellate cells(HSCs)remains a central event in fibrosis,complemented by other sources of matrix-producing cells,including portal fibroblasts,fibrocytes and bone marrow-derived myofibroblasts.These cells converge in a complex interaction with neighboring cells to provoke scarring in response to persistent injury.Defining the interaction of different cell types,revealing the effects of cytokines on these cells and characterizing the regulatory mechanisms that control gene expression in activated HSCs will enable the discovery of new therapeutic targets.Moreover,the characterization of different pathways associated with different etiologies aid in the development of disease-specific therapies.This article outlines recent advances regarding the cellular and molecular mechanisms involved in liver fibrosis that may be translated into future therapies.The pathogenesis of liver fibrosis associated with alcoholic liver disease,non-alcoholic fatty liver disease and viral hepatitis are also discussed to emphasize the various mechanisms involved in liver fibrosis.
文摘Alcoholic liver disease(ALD)is a leading cause of liver disease and liver-related deaths globally,particularly in developed nations.Liver fibrosis is a consequence of ALD and other chronic liver insults,which can progress to cirrhosis and hepatocellular carcinoma if left un-treated.Liver fibrosis is characterized by accumulation of excess extracellular matrix components,including typeⅠcollagen,which disrupts liver microcirculation and leads to injury.To date,there is no therapy for the treatment of liver fibrosis;thus treatments that either prevent the accumulation of typeⅠcollagen or hasten its degradation are desirable.The focus of this review is to examine the regulation of typeⅠcollagen in fibrogenic cells of the liver and to discuss current advances in therapeutics to eliminate excessive collagen deposition.
基金Major Project of Shanghai Municipal S and T Commission,Grant/Award Number:19401972300Shandong Province Key R&D Program(Major Science and Technology Innovation Project),Grant/Award Number:2021CXGC010509+2 种基金Shanghai Key Laboratory of Traditional Chinese Clinical Medicine,Key Disciplines of Liver and Gall Bladder Diseases,Key Laboratory of Chronic Deficiency Liver Disease of the State Administration of Traditional Chinese Medicine of the People's Republic of China,Grant/Award Number:20DZ2272200Shanghai Key Specialty of Traditional Chinese Clinical Medicine,Grant/Award Number:shslczdzk01201Outstanding TCM reserve talents of Shanghai University of Traditional Chinese Medicine(2020)。
文摘Liver cirrhosis is a leading cause of death from liver‐related diseases accompanied by a variety of complications;however,hepatic fibrosis,an inevitable stage of cirrhosis,is possible to be reversed and cured.Hepatic stellate cells(HSCs)are the primary cells that secrete extracellular matrix in the liver and play a dominant role in the pathogenesis of hepatic fibrosis.Effective therapeutic approaches for reversing hepatic fibrosis aim at inhibiting the activation of HSCs and inducing their inactivation or death.This review highlights the mechanism by which traditional Chinese medicine(TCM)regulates the activity of HSCs and exerts antifibrotic effects,providing insights and prospects for the treatment of hepatic fibrosis with TCM.
文摘肝纤维化是继发于各种慢性肝损伤之后组织修复过程中的代偿反应,其发病实质是肝内细胞外基质(extracellular matrix,ECM)合成与降解动态平衡发生紊乱,最终导致ECM过度沉积。肝纤维化的发生与发展受到多种细胞因子及细胞内多种信号转导通路网络的调控,其中很多靶点在肝纤维化中的作用尚没有完全定论。近年来越来越多的研究证实细胞因子信号转导抑制分子-3(suppressor of cytokine signaling,SOCS-3)在肝纤维化的发生与发展过程中扮演着重要角色。SOCS-3可通过调控肝脏内炎症反应、细胞增殖活化、胰岛素抵抗、瘦素抵抗等影响肝脏疾病的发展进程。许多学者认为SOCS-3可作为肝纤维化疾病诊断、预测预后的生物分子指标以及治疗靶标。该文从SOCS-3系统概述、SOCS-3与肝纤维化关系、SOCS-3在防治肝纤维化中的作用等方面综述了SOCS-3在防治肝纤维化中的作用及研究进展。
